An unexpected product from attempted reductive etherification of a silyl alcohol with an aldehyde

Article abstract of DOI:10.1016/j.tet.2007.03.163

Reductive etherification, using BiBr₃/Et₃SiH, between two modified amino acids, one with a silyl alcohol side chain and one with an aldehyde side chain, gave, not the desired bis-amino acid, but a tetrahydrooxazine, in good yield.

Full text of DOI:10.1016/j.tet.2007.03.163

Tetrahedron 63 (2007) 6932–6937
An unexpected product from attempted reductive etherification
of a silyl alcohol with an aldehyde
*
Christopher G. H. White and Alethea B. Tabor
Department of Chemistry, UCL, 20, Gordon Street, London WC1H 0AJ, UK
Received 1 February 2007; revised 9 March 2007; accepted 29 March 2007
Available online 4 April 2007
Abstract—Reductive etherification, using BiBr3/Et3SiH, between two modified amino acids, one with a silyl alcohol side chain and one with
an aldehyde side chain, gave, not the desired bis-amino acid, but a tetrahydrooxazine, in good yield.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
could potentially provide an interesting conformational
constraint, we sought to synthesise the ether-linked bis-
amino acid 1 and use this in the solid-phase synthesis of
cyclic peptides with aliphatic ether linkages. We envisaged
that the key step in the synthesis would be the formation
of the ether linkage itself, using the reductive etherification
of a silyl alcohol with an aldehyde recently reported by
several groups for intermolecular7–9 and intramolecular10
etherification.
Many different approaches to generating short peptides with
defined conformational properties have been reported. One
important strategy is the synthesis of peptides where two
or more side chains are linked together. The synthesis of
such peptides has previously relied on the preparation of
a linear peptide, followed by the development of chemistry
for linking two side chains that would be both regioselective
and compatible with the underlying peptide.1–3
We have recently developed a complementary approach to
the synthesis of side-chain bridged peptides. This entails,
firstly, the synthesis of a bis-amino acid with the desired
side-chain link in place between the two Ca positions. The
bis-amino acid is protected at one end with a transient
(Fmoc) protecting group, whilst the NH2 and COOH groups
at the other end are protected with groups orthogonal to both
Fmoc and to the permanent tBu/Boc groups on other amino
acid side chains. These amino acids can then be incorporated
into the desired peptide by standard solid-phase methods,
with the desired bridge being generated by removal of the or-
thogonal protecting groups followed by on-resin cyclisation.
We have so far used this approach to synthesise peptides
bridged by aliphatic links,4 norlanthionine5 and lanthio-
nine.6
2. Results
To carry out the reductive etherification, a silyl alcohol frag-
ment 2 and an aldehyde 3 were required. It seemed expedient
to prepare both of these from aspartic acid. However, it was
important not to use the same protecting group chemistry
on the two fragments, as after the etherification reaction it
would be necessary to differentiate the two amino groups,
and likewise the two carboxyl groups. Careful choice of
protection for the a-COOH groups was also necessary. We
envisaged that the synthetic routes to both 2 and 3 would
have homoserine derivatives as key intermediates. These are
known to lactonise rapidly11 unless bulky a-COOH protect-
ing groups are employed.
The silyl alcohol was prepared in the following manner
(Scheme 1). Selective b-esterification12 of aspartic acid
afforded 4, followed by Boc protection to give 5 and a-
esterification to give 6. As the reduction of 6 with DIBAL
did not give a clean reaction, it was decided to install a sec-
ond Boc protecting group to remove any possibility of inter-
ference by the acidic NH.13 Accordingly, 6 was protected
under mild conditions14 to give 7,15 which was then reduced
using DIBAL15 to give alcohol 8.16 Silylation under standard
conditions17 gave the desired 9.
Constrained cyclic peptides with aliphatic ether linkages be-
tween two side chains have rarely been reported, probably
due to the difficulties inherent in forming the ether between
two amino acid side chains of a linear peptide. As this motif
Keywords: Reductive etherification; Cyclic aminal.
* Corresponding author. Tel.: +44 20 7679 4695; fax: +44 20 7679 7463;
e-mail: a.b.tabor@ucl.ac.uk
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.163

C. G. H. White, A. B. Tabor / Tetrahedron 63 (2007) 6932–6937
6933
H
H
mixed anhydride formation followed by NaBH4 gave the
homoserine derivative 18. This was stable indefinitely at
ꢀ20 ꢁC, however at room temperature in solution some
lactonisation was observed. Finally, Swern reaction19 of
18 afforded the desired aldehyde 19.
AlocNH
O
COOH
1
COOAl
NHFmoc
H
H
P1NH
OSiMe2tBu
O
H
COOP4
COOH
COOH
COOH
COOH
NHP3
COOP2
i
2
3
H
H2N
H
AlocHN
COOH
COOH
10
H
H2N
ii
i (60%)
O
O
COOMe
COOMe
H
ii
AlocHN
H
H3N
H
O
COOH
BocHN
COOH
5
11
-
4
Cl
iii (89% over
3 steps)
iii (71% over 2 steps)
COOFm
COOH
COOH
COOMe
H
H
COOMe
H
AlocHN
iv
H
AlocHN
COOFm
Boc2N
COOtBu
BocHN
COOtBu
(60%)
12
13
7
6
Scheme 2. (i) Allyl chloroformate, Na2CO3, H2O, rt, 24 h; (ii) Ac2O, THF,
reflux, 4 h; (iii) 9-fluorenylmethanol, iPr2EtN, THF, rt.
v (62%)
OH
OTBDMS
O
COOH
H
O
i
H
Boc2N
H
H
Boc2N
vi
BocHN COOH
BocHN
COOtBu
COOtBu
(98%)
O
9
8
15
14
Scheme 1. (i) SOCl2, MeOH, ꢀ10 ꢁC to rt; (ii) (Boc)2O, Na2CO3, THF/H2O
t
(2:1), rt, 48 h; (iii) BuOH, DCC, DMAP, CH2Cl2, 0 ꢁC to rt, 48 h; (iv)
ii (75% over 2 steps)
(Boc)2O, DMAP, MeCN, rt, 24 h; (v) DIBAL, THF, ꢀ45 ꢁC, 1 h; (vi)
TMDMS-Cl, DMF, imidazole, rt, 18 h.
A recent publication2b suggested that use of the Fm protect-
ing group at the a-COOH of homoserine would prevent the
inherent problem of lactonisation. As the Fm and tBu esters
are orthogonal, this appeared to be an ideal way to prepare
the aldehyde fragment from aspartic acid. A reported proce-
dure for synthesis of Boc-Asp-OFm18 involved conversion of
Boc-Asp-OH to its anhydride, followed by ring-opening with
Fm-OH to give predominantly the a-ester, which could be
separated from the b-ester by selective recrystallisation.
We initially wished to modify this procedure by using the
Aloc group on the a-NH2, as this was more useful for our
purposes. Heating Aloc-Asp-OH 10 with acetic anhydride
(Scheme 2) gave the anhydride 11, which was immediately
treated with 9-fluorenylmethanol to give a mixture of 12 and
13. Unfortunately, this mixture could not be separated by
either recrystallisation or by flash column chromatography.
We therefore reverted to the protecting group used in the
original paper. Dehydration of Boc-Asp-OH 14 to give the
intermediate anhydride 15 (Scheme 3) proceeded cleanly
using DIC; ring-opening with 9-fluorenylmethanol gave pre-
dominantly the desired regioisomer 16, which was isolated
pure after four recrystallisations in excellent yield. The Boc
group was then exchanged for the Aloc group to give 17, and
careful control of the reaction conditions ensured no trans-
esterification took place. Reduction of the free b-COOH via
iii, iv (96%
over 2 steps)
COOH
COOH
H
H
BocHN
COOFm
AlocHN
COOFm
16
17
v (73%)
OH
O
H
H
vi (52%)
H
AlocHN
COOFm
AlocHN
COOFm
19
18
Scheme 3. (i) DIC, iPr2EtN, THF, rt, 4 h; (ii) iPr2EtN, 9-fluorenylmethanol,
THF, 24 h; (iii) TFA/CH2Cl2 (1:1), Et3SiH, 0 ꢁC, 2.5 h; (iv) allyl chloro-
i
formate, NaHCO3, THF/H2O (1:1), 0 ꢁC, 2 h; (v) Pr2EtN, isobutylchloro-
formate, CH2Cl2, rt, 1 h, then MeOH, NaBH4, ꢀ78 ꢁC; (vi) (COCl)2,
DMSO, CH2Cl2, ꢀ78 ꢁC, 30 min, then 18 added, Et3N, warm to 0 ꢁC, 2 h.
We then attempted the reductive etherification reaction using
the previously reported procedure7,10 (Scheme 4). This gave
a product with four of the five protecting groups (Fm, Aloc,
tBu and a single Boc) present. However, careful inspection
of the spectroscopic data indicated that this was not the
desired ether-bridged bis-amino acid, 20, but the cyclic

6934
C. G. H. White, A. B. Tabor / Tetrahedron 63 (2007) 6932–6937
O
OTBDMS
Boc
N
H
H
H
H
i (69%)
H
Boc2N
H
tBuOOC
COOFm
NHAloc
Boc2N
O
COOFm
NHAloc
COOtBu
AlocHN
COOFm
H
H
COOtBu
O
9
19
21
20 : not formed
Scheme 4. (i) BiBr3, Et3SiH, MeCN, 24 h.
1,3-tetrahydrooxazine 21. We assume by analogy with our
previous work20 that two diastereoisomers are present, how-
ever the NMR spectrum was not well enough resolved to
allow this to be unambiguously determined or to allow the
ratio to be measured.
that can react with the oxonium ion, leading to 21. Clearly
the intramolecular cyclisation is much more rapid than re-
duction of 22 by triethylsilane, which would be the normal
course of this reaction. We observed no evidence for silane
reduction of the cyclic 1,3-tetrahydrooxazine 21 under these
conditions. Furthermore, reductive cleavage of 21 would in
all probability lead to cleavage of the C–O bond, affording
a secondary amine, via N-acetyliminium formation.21
3. Discussion
There has recently been some debate about the catalyst
formed during the reductive etherification of aldehydes us-
ing BiBr3/Et3SiH. Bajwa et al.7 hypothesised that the active
catalyst is Et3SiBr, formed in situ, acting as a Lewis acid cat-
alyst. In this mechanistic scheme, HBr would also be gener-
ated, but would be removed by reaction with the solvent,
acetonitrile. However, Evans et al.10 recently demonstrated
that the active species is unlikely to be Et3SiBr (which is
highly moisture-sensitive) as the reaction will also take place
It is also likely that the HBr is responsible for the deprotec-
tion of the first Boc group. Indeed, there is precedent for this
deprotection,22 whereas Boc groups are generally stable to
mild Lewis acids and can, in fact, be prepared using Lewis
acids.23 This reinforces the probability that the HBr formed
from the BiBr3 is not buffered by the acetonitrile, but instead
is present in the reaction mixture. We attempted to neutralise
the HBr formed with K2CO3, however as expected no reac-
tion took place under these conditions.
˚
in the presence of 1 equiv of H2O. Moreover, if 4 A molecular
sieves or the base 2,6-di-tert-butyl-4-methylpyridine (DTBMP),
which should sequester or quench HBr, was added, no reac-
tion takes place. It was therefore demonstrated that the reac-
tion most likely involves Brønsted acid catalysis by HBr.
4. Conclusions
During an attempted reductive etherification reaction be-
tween a silyl alcohol and an aldehyde, both derived from
protected amino acids, a 1,3-tetrahydrooxazine was unex-
pectedly formed instead of the desired ether. Although this
undesired reaction meant that this route to ether-bridged
bis-amino acids had to be abandoned, as it would be impos-
sible to convert the 1,3-tetrahydrooxazine to the desired
ether via a ring-opening reaction, the reaction has shed
It is probable, therefore, that the mechanism for the forma-
tion of 21 is as follows (Scheme 5). HBr catalyses the initial
formation of an adduct between silyl alcohol 9 and aldehyde
19 as shown previously. Loss of silanol then affords the oxo-
nium species 22. Concomitant deprotection of the first Boc
group by the HBr then gives an intramolecular nucleophile
2 BiBr3 + 3 Et3SiH
2 Bi(s) + 3 Et3SiBr + 3 HBr
O
t
OSiMe2 Bu
t
SiMe2 Bu
H
H
H
H
Boc2N
H
HBr
Boc2N
tBuOOC
O
COOFm
OH NHAloc
COOtBu
AlocHN
COOFm
tBuMe2SiOH
9
19
H
H
O
tBuOOC
H
H
COOFm
NHAloc
Boc2N
BocHN
O
COOFm
NHAloc
HBr
tBuOOC
22
Boc
N
H
tBuOOC
COOFm
NHAloc
H
H
O
21
Scheme 5.

C. G. H. White, A. B. Tabor / Tetrahedron 63 (2007) 6932–6937
6935
further light on the mechanism of reductive etherification
using BiBr3/Et3SiH. Finally, this reaction also represents a
direct and potentially useful route from chiral pool starting
materials to 1,3-tetrahydrooxazines, which are useful inter-
mediates in the synthesis of a number of N-heterocycles.21
Si(CH3)2C(CH3)3), 0.03 (6H, s, Si(CH3)2C(CH3)3); 13C
NMR (75 MHz, CDCl3) d 170.1, 152.4, 82.6, 81.1, 60.2,
55.9, 33.1, 28.0, 27.9, 26.0, 18.3 (Si(CH3)2C(CH3)3 not pres-
ent); IR (film) nmax 2979, 2956 (C–H), 1737 (C]O), 1705
;
512.30193, found 512.30246.
(C]O) cmꢀ1
HRMS calcd for [C24H47NO7SiNa]+
5. Experimental
5.1.3. a-Fluorenylmethyl-N-tert-butyloxycarbonyl-L-as-
partate 16.18 To a stirred solution of L-aspartic acid (20.0 g,
0.150 mol) and Na2CO3 (47.7 g, 0.450 mol, 3 equiv) in H2O
(1.0 L) at 0 ꢁC was added (Boc)2O (32.8 g, 0.150 mol,
1 equiv) over 20 min. After slow warming to room tempera-
ture the reaction was stirred for 24 h. The mixture was then
cooled to 0 ꢁC and acidified to pH 2.0 with 0.05 M KHSO4
before being extracted with EtOAc (5ꢂ150 mL). The or-
ganic layer was then washed with brine (3ꢂ200 mL), dried
(Na2CO3) and concentrated in vacuo to give N-tert-butyl-
oxycarbonyl-L-aspartic acid as a clear colourless oil, which
was used in the next step without further purification.
5.1. General procedures and materials
All reagents used for synthesis were purchased from com-
mercial suppliers. Reactions requiring anhydrous conditions
were carried out in oven-dried glassware under Ar. Solvents
were purified using activated alumina solvent drying col-
umns. NMR spectra were recorded on a Bruker AMX300
spectrometer, chemical shifts (d) are reported in parts per
million (ppm) using residual isotopic solvent as an internal
reference. Coupling constants (J) are reported in hertz
(Hz). Electrospray mass spectra were recorded on Micro-
mass Quattro LC, Thermo Finnegan MAT 900XP or VG
ZAB 2SE instruments, and fast atom bombardment mass
spectra on Thermo Finnegan MAT 900XP or VG ZAB
2SE instruments. IR spectra were recorded on a Shimadzu
FT-IR 8700.
To a stirred solution of N-tert-butyloxycarbonyl-L-aspartic
acid (10.0 g, 0.0429 mol) in dry THF (175 mL) under an
argon atmosphere was added DIC (7.32 mL, 0.0473 mol,
1.1 equiv) dropwise over 20 min. After 4 h the reaction mix-
ture was filtered through a dry sinter funnel and concentrated
to approximately 100 mL in vacuo. To the solution was
added 9-fluorenylmethanol (9.28 g, 0.0473 mol, 1.1 equiv)
5.1.1. tert-Butyl-N,N-bis(tert-butyloxycarbonyl)-L-homo-
serinate 8.16 To a solution of 713,15 (100 mg, 0.248 mmol)
in dry CH2Cl2 (8.0 mL) at ꢀ78 ꢁC under Ar was added
DIBAL (1.0 M solution in toluene, 520 mL, 0.521 mmol,
2.1 equiv) slowly over 8 min. The reaction mixture was
stirred for 1 h before being quenched with acetone (5.0 mL)
and then H2O (1.0 mL), allowed to warm to room tempera-
ture, dried (Na2SO4) and filtered through Celite. The solvent
was removed in vacuo and the residual oil purified by flash
column chromatography (silica gel, 20% EtOAc in hexane,
Rf¼0.30) to yield 8 as a thick colourless oil (91 mg, 98%);
[a]2D2 ꢀ23.3 (c 0.38, in CH2Cl2); 1H NMR (300 MHz,
CDCl3) d 4.90 (1H, dd, J¼9.5, 4.9 Hz, CH a), 3.68 (2H, m,
CH2 g), 2.30 (1H, m, CH2 b), 1.95 (1H, m, CH2 b), 1.46
(18H, s, 2ꢂNCOOC(CH3)3), 1.39 (9H, s, OCOC(CH3)3);
13C NMR (CDCl3, 75 MHz) d 170.9, 153.0, 83.6, 81.9,
59.8, 56.9, 32.9, 28.4, 28.3; IR (film) nmax 3543 (O–H),
2979, 2935, (C–H), 1747 (C]O), 1700 (C]O) cmꢀ1; ES+
C18H33NO7Na m/z [M+Na]+ 398; HRMS calcd for
[C18H33NO7Na]+ 398.21546, found 398.21600.
i
in one portion and then Pr2EtN (4.1 mL, 0.0452 mol,
1.05 equiv) dropwise over 20 min. The reaction was then
stirred for 24 h under argon before being diluted with tolu-
ene (50 mL) and quenched with AcOH (5 mL). The solution
was concentrated in vacuo until approximately 10 mL re-
mained and was then diluted with EtOAc (100 mL), washed
with 0.05 M KHSO4 (3ꢂ100 mL), saturated brine (3ꢂ
100 mL), dried (Na2SO4) and the solvent evaporated in
vacuo. After 24 h drying on a high vacuum line a pink solid
remained, which was subsequently dissolved in a minimum
amount of hot EtOAc and recrystallised by addition of hex-
ane. The filtered solid was then washed twice with cold ethyl
acetate to give crude 16. The filtrate was concentrated in va-
cuo and recrystallised another four times to give 16 as a solid
(13.2 g, 75%), mp 138–142 ꢁC [lit.18b mp 156 ꢁC]; Rf¼0.1–
0.3 (silica gel, 50% EtOAc in hexane); [a]2D0 +19.1 (c 0.45, in
MeOH) lit.18b [a]D20 +15.2 (c 1.00, in THF); 1H NMR
(300 MHz, CDCl3/DMSO (9:1)) d 7.45 (2H, m, CH Ar),
7.26 (2H, m, CH Ar), 7.10 (2H, t, J¼7.4 Hz, CH Ar), 6.98
(2H, t, J¼7.4 Hz, CH Ar), 5.74 (1H, br d, J¼9.0 Hz, NH),
4.30 (1H, m, CH a), 4.02 (2H, m, COOCH2CHAr), 3.88
(1H, d, J¼7.2 Hz, COOCH2CHAr), 2.66 (1H, dd, J¼17.2,
5.2 Hz, CHH b), 2.43 (1H, m, CHH b), 1.11 (9H, s,
NCOOC(CH3)3); 13C NMR (75 MHz, CDCl3/DMSO)
d 171.8, 171.3, 155.3, 143.4, 140.9, 127.7, 127.1, 125.0,
119.8, 82.5, 67.3, 49.9, 46.4, 42.7, 28.2; IR (Nujol mull)
nmax 2650–3300 (broad, COOH), 3290 (N–H), 2952, 2922
(C–H), 1737 (C]O), 1504 (C]C, Ar) cmꢀ1; HRMS calcd
for [C23H25NO6Na]+ 434.15795, found 434.15697.
5.1.2. tert-Butyl-N,N-bis(tert-butyloxycarbonyl)-L-homo-
serinate tert-butyldimethylsilyl ether 9. To a solution of
8 (500 mg, 1.33 mmol) in dry DMF (0.5 mL) was added
t
imidazole (26 mg, 3.33 mmol, 2.5 equiv) and BuMe2SiCl
(260 mg, 1.8 mmol, 1.35 equiv). The resulting solution
was stirred for 18 h under Ar before being diluted with sat-
urated brine (20 mL) and ethyl acetate (20 mL). The organic
layer was then washed with saturated brine (2ꢂ50 mL),
dried (Na2SO4) and concentrated in vacuo. The residual oil
(0.98 g) was purified by flash column chromatography (sil-
ica gel, 5% EtOAc, 0.001% Et3N in hexane, Rf¼0.25) to
yield 9 as a clear colourless oil (640 mg, 98.4%); [a]D20
+27.7 (c 1.1, in CH2Cl2); 1H NMR (300 MHz, CDCl3)
d 4.90 (1H, dd, J¼8.6, 5.3 Hz, CH a), 3.67 (2H, m, CH2
g), 2.34 (1H, m, CH2 b), 2.00 (1H, m, CH2 b), 1.49 (18H,
s, NCOC(CH3)3), 1.43 (9H, s, OCOC(CH3)3), 0.87 (9H, s,
5.1.4. a-Fluorenylmethyl-N-allyloxycarbonyl-L-aspar-
tate 17. To a solution of CH2Cl2/TFA (1:1, 5.0 mL) at
0 ꢁC was added 16 (200 mg, 0.486 mmol). The mixture
was stirred at this temperature for 2.5 h before being poured
into ether (300 mL) and cooled to ꢀ23 ꢁC in the freezer
overnight. After this time a solid precipitate was formed,

6936
C. G. H. White, A. B. Tabor / Tetrahedron 63 (2007) 6932–6937
which was isolated by filtration. The filtrate was diluted with
hexane (100 mL) and again cooled to ꢀ23 ꢁC in the freezer
overnight to produce more solid. The solid was isolated by
filtration and this process was performed once more to yield
a-fluorenylmethyl-L-aspartate, which was used crude in the
following reaction.
(1H, m, CH2 b); 13C NMR (75 MHz, CDCl3) d 172.5,
156.6, 143.6, 141.3, 132.5, 127.9, 127.2, 125.0, 120.1,
118.0, 67.1, 66.0, 58.5, 51.7, 46.8, 34.9; IR (film) nmax
3419 (N–H), 3533 (O–H), 2899 (C–H), 1758 (C]O),
1683 (C]C), 1576 (C]C, Ar); HRMS calcd for
[C22H23NO5Na]+ 404.14738, found 404.14640.
To a solution of a-fluorenylmethyl-L-aspartate (270 mg,
0.657 mmol) and NaHCO3 (330 mg, 3.94 mmol, 6 equiv)
in H2O/THF (1:1, 16 mL) at 0 ꢁC was added allyl chlorofo-
mate (67 mL, 0.723 mmol, 1.1 equiv) with stirring. After 2 h
the reaction was quenched by careful addition of 0.05 M
KHSO4 (20 mL) and diluted with EtOAc (50 mL). The
organic layer was washed with 0.05 M aqueous KHSO4
(3ꢂ40 mL), saturated brine (3ꢂ40 mL), dried (Na2SO4)
and the solvent removed in vacuo to give a thick oil. Purifi-
cation by flash column chromatography (silica gel, 1%
AcOH, 50% EtOAc in hexane (Rf¼0.1–0.3 (silica gel,
50% EtOAc in hexane))) provided 17 as a cloudy pink crys-
talline glass, mp 68 ꢁC (249 mg, 96%); [a]2D0 ꢀ16.7 (c 0.59,
5.1.6. 2-(S)-Allyloxycarbonylamino-4-oxo-butyric acid
fluorenylmethyl ester 19. To a solution of oxalyl chloride
(233 mL, 2.76 mmol, 1.5 equiv) in dry CH2Cl2 (0.50 mL)
at ꢀ78 ꢁC was added dropwise DMSO (145 mL, 2.76 mmol,
1.5 equiv). The resulting solution was stirred for 30 min
at this temperature before a solution of 18 (700 mg,
1.84 mmol) dissolved in CH2Cl2 (2.0 mL) was added drop-
wise over 10 min. After 30 min Et3N (1.28 mL, 9.2 mmol,
5 equiv) was added and the reaction was warmed to 0 ꢁC.
After 2 h the solution was quenched with 0.1 M KHSO4
(20 mL) and allowed to warm to room temperature. The re-
sulting solution was diluted with CH2Cl2 (100 mL) and the
organic layer washed with 0.1 M KHSO4 (3ꢂ75 mL), dried
(Na2SO4) and concentrated in vacuo. The residual oil
(650 mg) was purified by flash column chromatography (sil-
ica gel, 30% EtOAc in hexane, Rf¼0.35) to yield 19 as a
dusty brown solid (545 mg, 52%), mp 110 ꢁC; [a]D20 +63.2
1
in MeOH); H NMR (300 MHz, CDCl3) d 8.25 (1H, br s,
COOH), 7.73 (2H, d, J¼7.5 Hz, CH Ar), 7.53 (2H, t,
J¼6.6 Hz, CH Ar), 7.38 (2H, m, CH Ar), 7.28 (2H, m, CH
Ar), 5.89 (2H, m, NH, CH2CH]CH2), 5.35–5.2 (2H, m,
CH2CH]CH2), 4.68 (1H, m, CH a), 4.66 (2H, m,
CH2CH]CH2), 4.54 (2H, m, COOCH2CHAr), 4.22 (1H,
t, J¼6.3 Hz, COOCH2CHAr), 2.89 (1H, dd, J¼17.7,
4.5 Hz, CHH b), 2.71 (1H, dd, J¼17.7, 4.5 Hz, CHH b);
13C NMR (75 MHz, CDCl3/DMSO) d 175.7, 170.7, 156.0,
143.4, 141.3, 132.4, 127.9, 127.2, 124.9, 120.0, 118.2,
67.7, 66.2, 50.2, 46.7, 36.3; IR (Nujol mull) nmax 2650–
3200 (broad, COOH), 3305 (N–H), 2952, 2922 (C–H),
1747 (C]O), 1645 (C]C),1506 (C]C, Ar); ES+
C22H21NO6Na m/z [M+Na]+ 418; HRMS calcd for
[C22H22NO6]+ 396.14471, found 396.14642.
1
(c 0.35, in CH2Cl2); H NMR (300 MHz, CDCl3) d 9.50
(1H, s, C(]O)H), 7.76 (2H, d, J¼7.5 Hz, CH Ar), 7.54
(2H, m, CH Ar), 7.41–7.25 (4H, m, CH Ar), 5.89 (1H, m,
CH2CH]CH2), 5.61 (1H, d, J¼8.6 Hz, NH), 5.30–5.10
(2H, CH2CH]CH2), 4.62–4.53 (5H, m, CH2CH]CH2,
COOCH2CHAr, CH a), 4.23 (1H, t, J¼6.1 Hz, COOCH2-
CHAr), 2.9 (2H, m, CH2 b); 13C NMR (75 MHz, CDCl3)
d 199.0, 170.6, 155.8, 143.4, 141.3, 132.4, 127.9, 127.2,
124.9, 120.1, 118.1, 67.3, 66.1, 49.0, 46.7, 45.7; IR (Nujol
mull) nmax 3305 (N–H), 2952, 2922 (C–H), 1737 (C]O),
1712 (C]O), 1645 (C]C), 1531 (C]C, Ar); HRMS calcd
for [C22H21NO5Na]+ 402.13174, found 402.13277.
5.1.5. Fluorenylmethyl-N-allyloxycarbonyl-L-homoseri-
nate 18. To a stirred solution of 17 (1.7 g, 4.30 mmol) in
dry CH2Cl2 (10.0 mL) was added isobutyl chloroformate
(614 mL, 4.73 mmol, 1.1 equiv) dropwise over 5 min, fol-
lowed by N-methylmorpholine (373 mL, 4.30 mmol,
1 equiv). The reaction was stirred under argon at room tem-
perature for 30 min and then cooled to ꢀ78 ꢁC before
NaBH4 (325 mg, 8.6 mmol, 2 equiv) was added in one por-
tion, followed by dropwise addition of MeOH (10.0 mL)
over 10 min. After 1.5 h the reaction was quenched by addi-
tion of AcOH (3.0 mL) and stirred for 30 min at ꢀ78 ꢁC be-
fore warming to room temperature and dilution with toluene
(40 mL). The solvents were removed in vacuo with the water
bath not exceeding 30 ꢁC to give a thick oil. This was
taken up in EtOAc (50 mL) and washed with 0.1 M HCl
(3ꢂ50 mL), saturated brine (3ꢂ50 mL), dried (Na2SO4)
and the solvent evaporated in vacuo to yield a viscous oil.
This was purified by flash column chromatography (silica
gel, 40% EtOAc in hexane (Rf¼0.25 (silica gel, 50% EtOAc
in hexane))) to give 18 as a clear colourless oil (1.3 g, 73%);
[a]2D0 ꢀ84.7 (c 0.46, in CH2Cl2); 1H NMR (300 MHz,
CDCl3) d 7.73 (2H, d, J¼7.5 Hz, CH Ar), 7.57 (2H, m,
CH Ar), 7.36 (2H, m, CH Ar), 7.30 (2H, m, CH Ar), 5.89
(2H, m, NH, CH2CH]CH2), 5.37–5.18 (2H, m,
CH2CH]CH2), 4.57–4.43 (5H, m, CH2CH]CH2,
COOCH2CHAr, CH a), 4.21–4.09 (1H, br m, COOCH2-
CHAr), 3.63 (2H, m, CH2OH), 2.03 (1H, m, CH2 b), 1.69
5.1.7. Coupling reaction between tert-butyl-N,N-bis(tert-
butyloxycarbonyl)-L-homoserinate tert-butyldimethyl-
silyl ether 9 and 2-(S)-allyloxycarbonylamino-4-oxo-
butyric acid fluorenylmethyl ester 19. To a stirred solution
of 9 (56 mg, 0.114 mmol) in MeCN (0.5 mL) at room tem-
perature was added Et3SiH (27 mL, 0.171 mmol, 1.5 equiv).
After 5 min BiBr3 (34.0 mg, 0.076 mmol, 0.67 equiv) was
added. A solution of 19 (65 mg, 0.171 mmol, 1.5 equiv) in
MeCN (0.5 mL) was then added and the solution stirred
for 24 h. The reaction was diluted with EtOAc (50 mL)
and then washed with Na2CO3 (2ꢂ50 mL), dried (Na2SO4)
and concentrated in vacuo. The residual oil was purified by
flash column chromatography (silica gel, 20% EtOAc in
hexane, Rf¼0.17) to yield 21 as a clear colourless oil
20
1
(50.2 mg, 69.1%); [a]D +11.2 (c 0.62, in CH2Cl2); H
NMR (300 MHz, CDCl3) d 7.85 (2H, m, CH Ar), 7.60
(2H, d, J¼7.1 Hz, CH Ar), 7.37 (2H, m, CH Ar), 7.26 (2H,
m, CH Ar), 5.92 (1H, m, CH2CH]CH2), 5.87 (1H, m,
NH), 5.44 (1H, m, AlocNHCHCH2CH(O)NBoc) 5.28–
5.18 (2H, m, CH2CH]CH2), 4.71 (1H, br s, tBuOOCCHN-
Boc), 4.58–4.48 (5H, m, CH2CH]CH2, COOCH2CHAr,
AlocNHCHCH2CH(O)NBoc), 4.29 (1H, br m, COOCH2-
t
CHAr), 3.75 (2H, m, BuOOCCHCH2CH2O), 2.25–2.20
(2H, m, AlocNHCHCH2CH(O)NBoc, tBuOOCCHCH2-
CH2O), 2.10–2.02 (2H, m, AlocNHCHCH2CH(O)NBoc,
tBuOOCCHCH2CH2O), 1.41 (18H, s, NCOC(CH3)3,

C. G. H. White, A. B. Tabor / Tetrahedron 63 (2007) 6932–6937
6937
OCOC(CH3)3); 13C NMR (75 MHz, CDCl3) d 172.1, 171.4,
156.0, 153.4, 143.6, 141.3, 132.7, 127.8, 127.2, 125.1, 120.0,
117.8, 82.0, 81.0, 67.6, 65.8, 64.3, 58.1, 51.7, 46.9, 34.4,
34.2, 28.3, 27.9; HRMS calcd for [C35H44N2O9Na]+
659.29444, found 659.29494.
7. Bajwa, J. S.; Jiang, X.; Slade, J.; Prasad, K.; Repic, O.;
Blacklock, T. J. Tetrahedron Lett. 2002, 43, 6709–6713.
8. Jiang, X.; Bajwa, J. S.; Slade, J.; Prasad, K.; Repic, O.;
Blacklock, T. J. Tetrahedron Lett. 2002, 43, 9225–9227.
9. Iwanami, K.; Seo, H.; Tobita, Y.; Oriyama, T. Synthesis 2005,
183–186.
10. Evans, P. A.; Cui, J.; Gharpure, S. J. Org. Lett. 2003, 5, 3883–
3885.
Acknowledgements
11. Rudolph, J.; Hannig, F.; Theis, H.; Wischnat, R. Org. Lett.
2001, 3, 3153–3155.
We thank the EPSRC for a DTA studentship to C.G.H.W.
12. Schwarz, H.; Bumpus, F. M.; Page, I. H. J. Am. Chem. Soc.
1957, 79, 5697–5703.
References and notes
13. Padron, J. M.; Kokotos, G.; Martin, T.; Markidis, T.; Gibbons,
W. A.; Martin, V. S. Tetrahedron: Asymmetry 1998, 9, 3381–
3394.
1. Ring-closing metathesis to form carba-bridged peptides: (a)
Miller, S. E.; Blackwell, H. E.; Grubbs, R. H. J. Am. Chem.
Soc. 1996, 118, 9606–9614; (b) Kasmaier, U.; Maier, S. Org.
Lett. 1999, 1, 1763–1766; (c) Schmiedeberg, N.; Kessler, H.
Org. Lett. 2002, 4, 59–62; (d) Stymiest, J. L.; Mitchell, B. F.;
Wong, S.; Vederas, J. C. J. Org. Chem. 2005, 70, 7799–7809.
2. Lantibiotics and other thioether-bridged peptides: (a) Burrage,
S.; Raynham, T.; Williams, G.; Essex, J. W.; Allen, C.; Cardno,
M.; Swali, V.; Bradley, M. Chem.—Eur. J. 2000, 6, 1455–1466;
(b) Campiglia, P.; Gomez-Monterrey, I.; Longobardo, L.;
Lama, T.; Novellino, E.; Grieco, P. Tetrahedron Lett. 2004,
45, 1453–1456.
14. Grehn, L.; Gunnarson, K.; Ragnarsson, U. Acta Chem. Scand.
1986, B40, 745–750.
15. Cox, R. J.; Gibson, J. S.; Martin, M. B. M. ChemBioChem
2002, 3, 874–886.
16. Roberts, J. L.; Chan, C. Tetrahedron Lett. 2002, 43, 7679–7682.
17. Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94,
6190–6191.
18. (a) Crozet, Y.; Wen, J. J.; Loo, R. O.; Andrews, P. C.; Spatola,
A. F. Mol. Divers. 1998, 3, 261–276; (b) Spatola, A. F.; Crozet,
Y.; deWit, D.; Yanagisawa, M. J. Med. Chem. 1996, 39, 3842–
3846.
3. For reviews of the synthesis of vancomycin and related aryl-
bridged peptides, see: (a) Lloyd-Williams, P.; Giralt, E.
Chem. Soc. Rev. 2001, 30, 145–157; (b) Kahne, D.;
Leimkuhler, C.; Wei, L.; Walsh, C. Chem. Rev. 2005, 105,
425–448; (c) Feliu, L.; Planas, M. Int. J. Pept. Res. Ther.
2005, 11, 53–97.
4. Alexander McNamara, L. M.; Andrews, M. J. I.; Mitzel, F.;
Siligardi, G.; Tabor, A. B. J. Org. Chem. 2001, 66, 4585–4594.
5. Mustapa, M. F. M.; Harris, R.; Esposito, D.; Chubb, N. A. L.;
Mould, J.; Schultz, D.; Driscoll, P. C.; Tabor, A. B. J. Org.
Chem. 2003, 68, 8193–8198.
19. (a) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651–1660;
(b) Tidwell, T. T. Synthesis 1990, 857–870.
20. Rae, A.; Aliev, A. E.; Anderson, J. E.; Castro, J. L.; Ker, J.;
Parsons, S.; Stchedroff, M.; Thomas, S.; Tabor, A. B.
J. Chem. Soc., Perkin Trans. 1 1999, 1933–1941.
21. For recent references, see, e.g., (a) Diness, F.; Beyer, J.; Meldal,
M. Chem.—Eur. J. 2006, 12, 7959–7962; (b) Nielsen, T. E.;
Meldal, M. J. Comb. Chem. 2005, 7, 599–610; (c) Nielsen,
T. E.; Meldal, M. J. Org. Chem. 2004, 69, 3765–3773.
22. Lesk, A.; Nudelman, A. Synth. Commun. 1999, 29, 1405–1408.
23. Sharma, G. V. M.; Reddy, J. J.; Lakshmi, P. S.; Krishna, P. R.
Tetrahedron Lett. 2004, 45, 6963–6965.
6. Bregant, S.; Tabor, A. B. J. Org. Chem. 2005, 70, 2430–2438.